Sajeev Menon MD ADRENAL INSUFFICIENCY? FATIGUE? OUTLINE OBJECTIVES PATIENT 1 PATIENT 1 : CLINICAL COURSE

Transcription

1 ADRENAL INSUFFICIENCY? FATIGUE? Sajeev Menon MD Endocrinologist KCIM OBJECTIVES OUTLINE Review primary and adrenal insufficiency including clinical and laboratory findings To appropriately interpret the results of basal and dynamic tests of adrenal function. Discuss the treatment of adrenal insufficiency including new options List the drugs that interfere with the HPA axis and cortisol metabolism Discuss Relative Adrenal Insufficiency and dispel the myth of Adrenal Fatigue Four case studies in the inpatient and outpatient settings - which address the learning objectives. PATIENT 1 PATIENT 1 : CLINICAL COURSE 17 yr old Caucasian male Collapses in London in 1947 Hypotension, Na 129 meq/l, K 4.9 meq/l Hx of diarrhea and weight loss Evaluated at Mayo clinic, diagnosed to have Addison s disease He has one year to live Deoxycorticosterone acetate (DOCA) pellets under his skin every 3 months : introduction of cortisone (Kendall/Hench at Mayo Clinic) 1954: Archives of Surgery report after back surgery 1955: BMR -15, compatible with hypothyroidism. Younger sister develops Addison s disease 1963: Dies of GSW. Post mortem: no adrenal tissue 1

2 SYMPTOMS OF ADRENAL INSUFFICIENCY HYPERPIGMENTATION Weakness, fatigue 100% Anorexia 100% Nausea 86% Vomiting 75% Abdominal Pain 31% Salt Craving 16% Postural dizziness 12% Muscle or joint pain 6-12 % 2

3 HYPERPIGMENTATION BIOCHEMICAL DIAGNOSIS OF PAI Paired cortisol and ACTH Serum cortisol < 5 mcg/dl Plasma ACTH >2 x upper normal Elevated renin/pra Low DHEA / DHEAS PAI: OTHER TYPICAL FINDINGS ADDITIONAL DIAGNOSTIC TESTS Hyponatremia 88% (low cortisol) Hyperkalemia 64% (low aldosterone) Hypercalcemia 6% Azotemia 55% Mild anemia 40% Eosinophilia 17% Lymphocytosis Varies Cosyntropin Stimulation Test mcg ACTH IM or IV min: >18-20 mcg/dl Normal Low dose Cosyntropin Test (1 mcg) - Not recommended ADDITIONAL DIAGNOSTIC TESTS ANTIBODIES Insulin Tolerance Test mcg/kg Regular insulin IV bolus Glucose < 40 mg/dl and Cortisol > 18 mcg/dl Metyrapone test (11 beta hydroxylase inhibitor) 30 mg/kg p.o at Labs Deoxycortisol > 7 mcg/dl - Normal - Cortisol < 5 mcg / dl - Required to fail 3

4 DIAGNOSTIC ALGORITHM TREATMENT OF ADRENAL INSUFFICIENCY Adrenal crisis is a life threatening emergency and requires immediate treatment. The goal of treatment is correction of hypotension and reversal of electrolyte abnormalities and cortisol deficiency. IVF (NS), IV HCN Mineralocorticoid administration is not necessary in the acute setting. HCN in 2-3 divided doses is the drug of choice for management of chronic primary adrenal insufficiency. TREATMENT OF ADRENAL INSUFFICIENCY TREATMENT OF ADRENAL INSUFFICIENCY Chronic management invariably requires Fludrocortisone. Adjust the dose to lower PRA to the upper normal range. ACTH measurement is usually not helpful or necessary. UFC is not completely reliable to assist in HCN dose titration. DHEA maybe helpful is some women. The adrenal glands only produce 8-12 mg (6-7 mg/sq m/day) of cortisol daily. Doses of HCN mg daily in divided doses is adequate in most patients. There is no physiologic prednisone dose. SERUM CORTISOL PROFILE : PLENADREN VS HC SUBCUTANEOUS PUMP THERAPY 4

5 PATIENT 2 SALIVARY CORTISOL GRAPH 20 yr old Caucasian male Seems quite nervous Has palpitations, anxiety with panic attacks, fatigue Normal exam and BP. Weight has been stable. BMI 22. Integrative Family Wellness Center : Salivary cortisol profile showed adrenal fatigue. Treated with adrenal support (no active steroids listed) PATIENT 2 PATIENT 2 : NEXT BEST TEST? Labs : Normal CBC and CMP. Morning serum cortisol : 1.4 mcg/dl CST (250 mcg IV) Cortisol increased from 1.8 to 11.6 ACTH at baseline was < 5 pg/ml FT4, IGF-1, TSH, PL and total testosterone - WNL Pituitary MRI was done and found to be normal. Subsequently other tests were considered: -Long chain fatty acid profile -21 hydroxylase antibodies -Synthetic glucocorticoid screen -17 hydroxyprogesterone 5

6 PATIENT 2 : CLINICAL COURSE A few days later, his father calls to inform that patient was found to be abusing Buprenorphine. OPIOID INDUCED ADRENAL INSUFFICIENCY Heroin addicts (60-70%) have impaired cortisol response to stimulation. Methadone attenuates ACTH / Cortisol response to Naloxone. Clinically significant adrenal insufficiency / crisis seems rare. OR is it? There are 17,000 deaths annually from narcotic overdose. DRUG INDUCED ADRENAL INSUFFICIENCY Corticosteroids and progesterone (medroxy progesterone) Opioids Adrenostatic/lytic and GR antagonist Ipilimumab (CTLA-4 Mab, can cause hypophysitis) Psychotropic drugs: benzodiazepine, atypical antipsychotics etc PATIENT 3 PATIENT 3 : LAB TESTS 75 yr old, diabetic gentleman Admitted with lobar pneumonia a week ago Developed hypotension and oliguria 36 hours ago Transferred to ICU Intubated, broad spectrum ABX, IVF, Insulin gtt Glucose 128 mg/dl Na 133 meq/l K 3.7 meq/l Cl 94 meq/l HCO3 28 meq/l Ca 7.9 mg/dl Albumin 1.9 mg/dl 6

7 PATIENT 3 : LAB TESTS RELATIVE ADRENAL INSUFFICIENCY Serum cortisol 11 mcg/dl at baseline and 17.5 mcg/dl after stimulation. Aldosterone 3.5 ng/dl PRA 12 ng/ml/h ACTH 17 pg/ml This concept was based on an initial report by Rothwell in 1991 Definition: Incremental cortisol response to Cosyntropin < 9 mcg/dl Important prognostic feature in septic shock Subsequent reports used the same definition Used to define need for HC therapy (Annane et al; JAMA 288:862;2002) (Serious limitation most patients responding to HCN had received Etomidate) Rapid increase in similar publications *Arafah B; JCEM : 91: 3725 PATIENT 3 : WHAT IS THE BEST NEXT STEP? 1. Administer hydrocortisone and fludrocortisone 2. Initiate high dose dexamethasone MEASURE FREE CORTISOL Measuring free cortisol in critical illness may identify patients with true adrenal insufficiency and distinguish them from patients with low cortisol related to decreased binding proteins. 3. Measure free cortisol 4. Obtain pituitary MRI However this test is not available in most labs and even if available might not be reported back for a few days. Raff H, et al. Endocrine 34: 68-74, 2008 SM1 FREE CORTISOL FREE CORTISOL LEVELS DURING CRITICAL ILLNESS PREDICT MORTALITY Free cortisol levels during critical illness predict mortality 7

8 Slide 42 SM1 Sajeev, 10/15/2016

9 PATIENT 3 : CORTICUS TRIAL Although ACTH levels actually decline, decreased cortisol clearance and slightly increased production rates sustain cortisol levels during critical illness and may require a dose adaptation when HCN treatment is considered. Despite elevated PRA, low aldosterone is seen in 20% of critically ill patients. DHEA levels may also be subnormal. 499 ICU patients with septic shock were randomized. 233 (47%) had abnormal CST, defined as <9 mcg/dl increase in total cortisol. (30 increasing to 32 was considered abnormal and 28 increasing to 46 was considered normal) 125 received HCN for 11 days. 108 received placebo. There was no decrease in mortality with HCN. *Sprung CL et al NEJM 2008: 358: CORTICUS TRIAL Hydrocortisone reversed shock more quickly BUT caused more superinfection and new sepsis / shock. It had no impact on mortality or length of stay Cosyntropin testing did not predict responsiveness to HC Despite that study, some intensivists continue to use the term : relative adrenal insufficiency. RELATIVE ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS Weak scientific evidence Iatrogenic steroids, propofol, opioids, psychotropic meds Total cortisol is misleading due to low CBG Steroid therapy is unhelpful High steroid levels = worse prognosis The adrenal glands never fatigue! RELATIVE ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS HPA axis is generally highly activated; not as well apparent from measurements of serum total cortisol levels. Secretion of other ACTH dependent steroids (DHEA) is also increased. When HCN is used, the therapeutic response is not typical of that in adrenal insufficiency. NEW ONSET ADRENAL INSUFFICIENCY IN THE ICU It does exist BUT.. NOT AS CURRENTLY DEFINED It is a rare event Can be iatrogenic (e.g. etomidate) Should be considered for patients at risk. 8

10 DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS Diagnosis is difficult Always suspect it in patients at risk Always look for a cause Consider limitations of tests (serum cortisol) Can rely on random serum cortisol as long as binding protein abnormalities are taken into account Take advantage of ACTH dependent steroids (DHEAS). Cosyntropin test is NOT necessary Serum free cortisol is desirable but not readily available Can rely on random serum total cortisol Recommendations are based on data in nearly 300 patients DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS DIAGNOSIS OF ADRENAL INSUFFICIENCY DURING CRITICAL ILLNESS In the absence of binding protein abnormalities: Expected total cortisol is often >15 mcg/dl If cortisol is 10-15, consider the diagnosis If cortisol is < 10, diagnosis is likely. If unclear, can treat and diagnose later When binding proteins are low: Cortisol should be at least > 11 If cortisol is 8-11, consider the diagnosis If level is <8, diagnosis is likely. TREATMENT OF ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS Principles of therapy Provide appropriate doses of glucocorticoids for the critical illness. No definitive studies regarding dosage Lower doses maybe effective based on data in critically ill patients with AI Recent data do show decreased cortisol clearance during critical illness. At times high doses may be needed to treat associated inflammatory processes. TREATMENT OF ADRENAL INSUFFICIENCY IN CRITICALLY ILL PATIENTS WITH KNOWN OR NEWLY DIAGNOSED ADRENAL INSUFFICIENCY CRITICAL ILLNESS WITHOUT SHOCK: Use HCN 25 mg Q 6 Hrs Taper as clinically indicated In patients with primary disease, add Fludrocortisone when total daily dose of HCN is < 50 mg/day CRITICAL ILLNESS WITH SHOCK: Use HCN 50 mg Q 6 Hrs Taper as clinically indicated No need for Fludrocortisone 9

11 HCN 25 mg IV every 6 hrs USE OF GLUCOCORTICOIDS IN PATIENTS WITH SEPTIC SHOCK BUT WITHOUT ADRENAL INSUFFICIENCY Data is limited. It is possible that HCN might benefit a small number of patients with septic shock and severe inflammatory response. GC therapy in this setting may represent pharmacologic therapy of an inflammatory disease. There are no available tests that can identify patients who might benefit from this therapy. Patients who received Etomidate should be treated with HCN for at least 24 hours. ADRENAL FUNCTION DURING CHRONIC STRESS AIDS patients PTSD Chronic Fatigue Syndrome PATIENT 4 Patient is a 46 year old Caucasian male He has a high stress job. Travels a lot. Doesn t sleep well. Reports anxiety, palpitations, near syncope and dizziness. Medical history is negative for any significant illness. Does not take any meds. Vitals: P 80 BP 130/74 BMI 29.6 Normal physical exam. Referred to Integrative Family Wellness Center 10

12 11

13 I HAVE ADRENAL INSUFFICIENCY SUMMARY: LIST OF DO S When someone tells you that. he or she probably does not! 99.9% is iatrogenic 100% should have weight loss Should have a Lazarean response to treatment. There is no such thing as Adrenal Fatigue. Corticosteroids dull pain. Do suspect exogenous GC Do suspect Narcotics Do determine etiology of primary adrenal insufficiency Do check Albumin in the ICU setting Do measure DHEAS for confirmation Do consider adrenal insufficiency for unexplained hyponatremia SUMMARY: LIST OF DON TS Don t accept adrenal fatigue as a diagnosis Don t diagnose Relative Adrenal Insufficiency Don t recommend CST in ICU Don t forget narcotics and GC Don t overtreat chronically Don t forget Fludrocortisone Don t follow ACTH in primary adrenal insufficiency Thank you! 12